Last year will be remembered for many things, many of them not good. But here's at least one flicker of hope: 2017 may go down as the year gene therapy finally turned a corner. In late December, the Food and Drug Administration announced its approval of the third gene therapy since August. These three therapies—two for treating cancer and one for treating a form of congenital blindness—are the first of their kind to pass muster with the FDA. And with hundreds of clinical trials for other gene therapies underway, they won't be the last. For decades, gene therapy was a pipe dream, symbolizing the unfulfilled promises of biomedical scientists who claimed that they could not just treat but actually cure disease by fixing genes. Those promises are finally beginning to be realized.
The logic behind gene therapy is simple. Many diseases are caused by a missing or defective gene; replace the broken gene with a working copy, and you cure the disease. But putting this logic into practice hasn't been so easy. For more than a century, scientists have cataloged disease-causing defective genes. In 1902, British physician Archibald Garrod deduced that an inherited disease called alkaptonuria was caused by a mutation that breaks a specific, but then-unknown metabolic enzyme. Half a century later, biochemist Vernon Ingram was the first to pinpoint the exact molecular cause of a genetic disease, when he discovered the specific molecular defect in the hemoglobin protein of people afflicted by sickle-cell disease. Finding such damaged genes, while not trivial, has however turned out to be much easier than fixing them. As Ingram later wrote about his 1956 discovery: "Entirely different approaches were needed to find a therapy [for sickle cell disease]; that took a long time, because they were not based on the molecular biology."
By the 1990s, scientists had developed the capability to make replacements for damaged genes, but they had no good way to deliver these replacements to the right cells inside a living patient. The most obvious delivery vehicles were viruses, since infiltrating cells is what viruses do best. But infecting a patient with a high dose of virus risks creating a toxic immune system response, which is what killed 18 year-old Jesse Gelsinger, a volunteer in a 1999 gene therapy trial. Gelsinger's widely publicized death was a major setback for gene therapy because it took researchers by surprise and vividly demonstrated the serious risks of the approach.
In spite of this setback, scientists continued to pursue gene therapy because, ultimately, it is the only way to directly cure a genetic disease. All drugs and other non-gene therapy treatments are indirect because they don't correct the underlying genetic cause. As a result, those who suffer from conditions like sickle-cell anemia and cystic fibrosis are dependent on a lifetime regimen of drugs—at least in the fortunate cases where effective drugs are available.
After nearly two decades of careful work, researchers are beginning to safely and reliably solve the problem of how to use viruses to deliver a replacement gene to a patient. The viruses are genetically altered so that they don't replicate inside a patient's body—meaning that, unlike the flu, these viruses can't be spread from person to person. Luxturna, the latest gene therapy approved by the FDA, relies on such viruses to carry a replacement gene into the retinas of patients with a certain form of congenital blindness. In two small trials published in December, viruses successfully delivered gene therapy to the blood cells of patients suffering from the two major types of hemophilia. In a November study, a different virus—optimized to target the central nervous system—successfully delivered a replacement gene into cells of 15 children suffering from spinal muscular atrophy, a neurodegenerative disease that is almost always fatal by age two. At 20 months, all 15 children were doing well. And in a March report, yet another type of virus was used in gene therapy administered to a 13-year-old boy suffering from sickle-cell disease. Fifteen months after treatment, he was largely free of symptoms.
For some diseases, it is more effective to make genetic changes to cells that have been isolated from a patient than to inject the patient with viruses. The two cancer-targeted gene therapies approved by the FDA, used against acute lymphoblastic leukemia and B-cell lymphoma, work like this: First, a cancer patient's immune system T-cells are removed and sent off to a lab, where a new gene is engineered into them. The T-cells are infused back into the patient, where the engineered gene helps the T-cells target cancer cells. A similar approach was used in a spectacular, last-ditch treatment in Germany to save the life of a seven-year-old child suffering from a severe genetic skin disease. This disease is caused by damage to a gene needed to anchor the skin in place, and patients frequently suffer from painful, extensive lesions all over their skin. When the child arrived at the hospital, he had lost over 80 percent of his outer layer of skin. Working with a small sample of the boy's skin cells, a team of German and Italian doctors corrected the mutation and then used the cells to grow sheets of replacement skin in the lab. After a series of surgical grafts, the boy now has healthy, genetically corrected skin over almost his entire body.
The United States federal database of clinical trials lists more than 300 ongoing gene therapy trials, and another 800 that are currently enrolling patients. The diseases covered by these trials range from rare genetic diseases to congestive heart failure, cancer, and HIV. While it's important not to over-hype the current state of gene therapy—many of the remarkable successes reported in the past year come from small, preliminary trials—the state of the field has clearly changed, and other FDA-approved gene therapies are sure to follow the first three. We can be confident in this because, once a particular gene therapy works for one disease, it shouldn't require many changes to apply that therapy to similar diseases. The gene therapy Luxturna repairs one particular gene in one form of retinal disease. But there are more than 200 known genes linked to similar retinal diseases, many of which could be repaired using a viral delivery method that is virtually identical to that of Luxturna.
Now that researchers have solved some key problems to make gene therapy work, society must solve the problem of how to pay for it. Pricing gene therapy poses a challenge both to drug companies and to insurance companies: Unlike a drug, which patients might take continually for years or decades, gene therapy is supposed to be a single-dose cure that lasts for a lifetime. How much is one dose of gene therapy worth if it prevents a child from going blind, or spares a hemophiliac the expense and suffering of a lifetime on drugs? On January 3rd, Spark Therapeutics, the company that makes Luxturna, announced that its therapy will cost $850,000—less than some had feared, but extremely expensive nonetheless.
Compared to the cost of a lifetime of drugs or disability accommodations, perhaps nearly $1 million for a cure isn't unreasonable. On the other hand, as more gene therapies reach the clinic, such astronomical prices could raise insurance premiums and put these cures out of reach for some. This is a serious problem—but a debate over the cost of cures for once-incurable diseases is one we should be happy to have.